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DEER Spectroscopy Measurements Reveal Multiple Conformations of HIV-1 SOSIP Envelopes that Show Similarities with Envelopes on Native Virions

Stadtmueller, Beth M. and Bridges, Michael D. and Dam, Kim-Marie and Lerch, Michael T. and Huey-Tubman, Kathryn E. and Hubbell, Wayne L. and Bjorkman, Pamela J. (2018) DEER Spectroscopy Measurements Reveal Multiple Conformations of HIV-1 SOSIP Envelopes that Show Similarities with Envelopes on Native Virions. Immunity, 49 (2). pp. 235-246. ISSN 1074-7613. PMCID PMC6104740. http://resolver.caltech.edu/CaltechAUTHORS:20180731-112023462

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Abstract

HIV-1 Envelope (Env) mediates viral-host membrane fusion after binding host-receptor CD4 and coreceptor. Soluble envelopes (SOSIPs), designed to mimic prefusion conformational states of virion-bound envelopes, are proposed immunogens for eliciting neutralizing antibodies, yet only static structures are available. To evaluate conformational landscapes of ligand-free, CD4-bound, inhibitor-bound, and antibody-bound SOSIPs, we measured inter-subunit distances throughout spin-labeled SOSIPs using double electron-electron resonance (DEER) spectroscopy and compared results to soluble and virion-bound Env structures, and single-molecule fluorescence resonance energy transfer (smFRET)-derived dynamics of virion-bound Envs. Unliganded SOSIP measurements were consistent with closed, neutralizing antibody-bound structures and shielding of non-neutralizing epitopes, demonstrating homogeneity at Env apex, increased flexibility near Env base, and no evidence for the intra-subunit flexibility near Env apex suggested by smFRET. CD4 binding increased inter-subunit distances and heterogeneity, consistent with rearrangements required for coreceptor binding. Results suggest similarities between SOSIPs and virion-bound Envs and demonstrate DEER’s relevance for immunogen design.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.immuni.2018.06.017DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6104740PubMed CentralArticle
ORCID:
AuthorORCID
Bjorkman, Pamela J.0000-0002-2277-3990
Additional Information:© 2018 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Open Access funded by Bill & Melinda Gates Foundation. Received 21 March 2018, Revised 15 May 2018, Accepted 28 June 2018, Available online 31 July 2018. We thank J. Vielmetter, H. Gao, and the Caltech Protein Expression Center for producing proteins, J. Keeffe and A. Voll for cloning assistance, M.E. Abernathy and H. Wang for making chemical structure and ET map figures, respectively, M. Murphy for assistance with other figures, C. Altenbach for advice on DEER acquisition and analysis, and members of the Bjorkman laboratory for critical reading of the manuscript. B.M.S. was supported by a Caltech Baxter Senior Post-doctoral fellowship. This research was supported by the NIH Grant HIVRAD P01 AI100148 (P.J.B.), the Bill and Melinda Gates Foundation [CAVD Grant OPP1124068 (P.J.B.)], the Jules Stein Professorship Endowment and NIH Grants R01 EY05216, T33 EY07026, and 5P41EB001980. Author Contributions: B.M.S. and P.J.B. designed the study; B.M.S., M.D.B., M.T.L. and W.L.H. designed DEER experiments and analyzed data; B.M.S. designed and produced spin-labeled proteins with assistance from K.-M.D. and K.E.H.-T.; M.D.B. collected and processed DEER data; B.M.S. and P.J.B. wrote the manuscript with contributions from all authors. The authors declare no competing interests.
Funders:
Funding AgencyGrant Number
Caltech Baxter Postdoctoral FellowshipUNSPECIFIED
NIHP01 AI100148
Bill and Melinda Gates FoundationOPP1124068
Jules Stein Professorship EndowmentUNSPECIFIED
NIHR01 EY05216
NIH Predoctoral FellowshipT33 EY07026
NIH5P41EB001980
Subject Keywords:HIV-1 Envelope; SOSIP; CD4; bNAbs; conformational dynamics; vaccine development; electron paramagnetic resonance; double electron-electron resonance (DEER) spectroscopy
PubMed Central ID:PMC6104740
Record Number:CaltechAUTHORS:20180731-112023462
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20180731-112023462
Official Citation:Beth M. Stadtmueller, Michael D. Bridges, Kim-Marie Dam, Michael T. Lerch, Kathryn E. Huey-Tubman, Wayne L. Hubbell, Pamela J. Bjorkman, DEER Spectroscopy Measurements Reveal Multiple Conformations of HIV-1 SOSIP Envelopes that Show Similarities with Envelopes on Native Virions, Immunity, Volume 49, Issue 2, 2018, Pages 235-246.e4, ISSN 1074-7613, https://doi.org/10.1016/j.immuni.2018.06.017. (http://www.sciencedirect.com/science/article/pii/S1074761318302991)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:88376
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:31 Jul 2018 18:36
Last Modified:27 Aug 2018 18:10

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